RESUMO
Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 microg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.
Assuntos
Antituberculosos/farmacocinética , Compostos Aza/farmacocinética , Glucanos/química , Glucanos/farmacocinética , Macrófagos Alveolares/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/farmacocinética , Animais , Antituberculosos/química , Área Sob a Curva , Compostos Aza/sangue , Compostos Aza/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Colônia Microbiana , Compostos de Dansil/química , Relação Dose-Resposta a Droga , Fluoroquinolonas , Glucanos/sangue , Meia-Vida , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Moxifloxacina , Quinolinas/sangue , Quinolinas/químicaAssuntos
Virus da Influenza A Subtipo H5N1/genética , Influenza Aviária/virologia , Animais , Sudeste Asiático/epidemiologia , Galinhas , DNA Complementar/química , DNA Complementar/genética , Hemaglutininas/genética , Virus da Influenza A Subtipo H5N1/classificação , Influenza Aviária/epidemiologia , Dados de Sequência Molecular , Neuraminidase/genética , Filogenia , Análise de Sequência de DNA , Sibéria/epidemiologia , PerusRESUMO
An approach combining virology with light and electron microscopy was used to study the organs of guinea pigs during nine serial passages of Ebola virus, strain Zaire. It was observed that the wild type of Ebola virus causes severe granulomatous inflammation in the liver and reproduces in the cells of the mononuclear phagocyte system (MPS). Based on morphological characterization, two types of virus-cell interactions were demonstrated. The obtained data evidenced for heterogeneity of the population of wild type of Ebola virus. The virus accumulated in the liver of the infected animals, and the lesions became more pronounced with passage. Degenerative changes appeared, and their severity was increased with passage in the other organs as well. The set of target cells diversified and, as a result, not only the MPS cells, but also hepatocytes, spongiocytes, endotheliocytes and fibroblasts became involved in the reproduction of Ebola virus. The possible role of granulomatous inflammation in the development of the adaptive mechanism of Ebola virus to guinea pigs is discussed.
